The role of genetic factors in alcoholism is well-established. Like most common diseases, it is likely that mutations at several or many different loci predispose to alcoholism. One mutation that may predispose to alcoholism is a mutation at nucleotide 1788 of the arylsulfatase A locus. A consequence of the amino acid alteration due to this mutation is that the enzyme lacks an oligosaccharide moiety and is metabolically labile in the cell. The arylsulfatase A activity is reduced in cells homozygous for this mutation. Alcoholic patients have an excess of homozygotes with this mutation compared with the prevalence observed in nonalcoholic populations. Acceptance of these previous findings has been limited by the fact that all population studies of genotype and disease frequency are vulnerable to undetected stratification. Confounders such as ethnic origins and social class can affect both the exposure (genotype) and the outcome (disease). This proposal is designed to study arylsulfatase A and other candidate genes for a possible relationship to alcoholism and behavioral/neuropsychological deficits without the influence of stratification confounders. The major hypothesis that candidate gene mutations are predisposing to alcoholism will be tested by comparing the frequency of such mutations or homozygosity for such mutations among patients with alcohol dependence to that in their sibs. A secondary goal of this research is to examine the relationship between the mutations and behavioral/neuropsychological deficits, particularly behavioral undercontrol and executive dysfunction.